Bacterial resistance to antibiotics is an increasingly recurrent phenomenon. Of grave concern has been the development of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Streptococcus epidermidis (MRSE) strains, which because of the phenomenon of cross-resistance, are now also resistant to the larger class of β-lactam antibiotics including the cephalosporins and carbapenems. Of even graver concern is the development of resistance in MRSA strains against the class of antibacterial agents known as fluoroquinolones. Several reports are known of MRSA strains displaying resistance to fluoroquinolone agents such as ciprofloxacin, sparfloxacin and even the more recently introduced trovafloxacin. In addition, for trovafloxacin and for newer introductions like grepafloxacin, moxifloxacin and gatifloxacin, a concern has been expressed about their checkered safety records. The use of trovafloxacin has been suspended or severely curtailed because of its association with liver side effects. Grepafloxacin was withdrawn worldwide because of severe cardiovascular side effects. The labelling on gatifloxacin and moxifloxacin warns that they may prolong the QTc interval on electrocardiograms in some patients.
The last line of defense against such fluoroquinolone-resistant MRSA strains is the class of glycopeptide antibiotics represented by vancomycin and teicoplanin. These glycopeptide antibiotics are, however, laden with several limitations. Vancomycin is encumbered with lack of oral bioavailability, nephrotoxic potential, toxic effects such as phlebitis and red-men syndrome. Moreover, the recent disturbing wide spread emergence of Vancomycin resistant enterococci (VRE) followed by the alarming reports of Vancomycin intermediate resistance Staphylococcus aureus (VISA) strains from Japan and USA have cast a shadow over the future of glycoside antibiotics in clinical practice. In time, there is a relatively wide-spread emergence of staphylococci, enterococci, pneumococci and streptococci, which have become resistant to currently used first-and second-line antibacterial agents such as penicillin, oxacillin, vancomycin and erythromycin (SENTRY Programme: Antimicrobial Agents & Chemotherapy 42 1762-1770, 1998).
Also, for primary skin infections such as impetigo and folliculitis, and for secondary infections in humans such as infected dermatitis, wounds and burns, as well as to eliminate nasal carriage of MRSA in healthcare workers and patients, a special antibiotic used topically is Mupirocin. Mupirocin has high in vitro anti-staphylococcal and anti-streptococcal activity. There has, however, been an increase of organisms, specially staphylococci, developing resistance to Mupirocin. The emergence of Mupirocin-resistant Methicillin-resistant Staphylococcus aureus (MRSA) in infected patients in different countries like Canada, Western Australia, UK, Spain and Switzerland is described in different references in the medical and scientific literature viz. J. Hosp. Infect. 39(1), 19-26 (1998); J. Hosp. Infect. 26(3), 157-165 (1994); Infect Control Hosp Epidemiol 17(2), 811-813 (1996); 38th Annual ICAAC Abstract C-75, 90 (1998); 38th ICAAC Abstract 12-25, 507 (1998).
Furthermore, Gram-positive pathogens such as Staphylococci, enterococci and Gram-negative pathogens E. coli, Klebsiella, Proteus, Serratia, Citrobacter and Pseudomonas, frequently encountered in urinary tract infections are susceptible to the known fluoroquinolones, such as ciprofloxacin, levofloxacin, ofloxacin and norfloxacin. The potency of these fluoroquinolones, however, markedly deteriorates under the acidic conditions likely to be encountered in urinary tract infections, rendering them inadequate.
Furthermore, multidrug-resistant (MDR) mycobacterial strains have emerged displaying resistance to first-line antimycobacterial agents such as rifampicin, pyrazinamide and INH etc. thus severely curtailing therapeutic options available for the management of infections due to such strains. Usually, the antimycobacterial drug regimen involves treatment spread over several months, and hence the drug has to be tolerated well by the patients. Among the fluoroquinolone antibiotics, sparfloxacin is reported to be highly active against mycobacteria. It is not quite suitable, however, for long-term therapy because of its potential to cause phototoxic side effects in humans and laboratory animals such as mice and guinea-pigs.
Furthermore, in the worldwide management of nosocomial infections, besides the problematic strains of staphylococci and enterococci, including MRSA, strains of Chryseobacteria have recently emerged as new members of nosocomial pathogens causing neonatal meningitis and pneumonia, as well as sepsis, in immuno-compromised patients being treated in intensive care units. Chryseobacteria are intrinsically resistant to β-lactam antibiotics including third-generation cephalosporins and carbapenems. These factors reduce the treatment options available to the clinicians.
The highly pressing need for other agents and methods of treatment for infections arising from such emerging resistant microorganisms, Gram-negative pathogens in acidic environments, mycobacteria and nosocomial pathogens thus assumes great significance.
Among other agents, one particular class of compounds the benzoquinolizine carboxylic acids are of particular relevance. Nadifloxacin is an example of a benzoquinolizine carboxylic acid. Nadifloxacin is racemic [(±)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H-5H-benzo[i,j]quinolizine-2-carboxylic acid and is disclosed in JP Patent No. 58,90,511 and U.S. Pat. No. 4,399,134. Nadifloxacin has an asymmetric carbon atom at the 5-position thereof. RS-(±)-Nadifloxacin comprises two optically active isomers. In describing an optically active compound, the prefixes R and S or D and L are used to denote the absolute configuration of the molecule about its chiral centre(s). The prefixes (+) and (−) or d and l are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. Compounds having a single chiral centre exist as a pair of enantiomers, which are identical except that they are non-superimposable mirror images of one another. A one-to-one mixture of enantiomers is often referred to as a racemic mixture. Racemic RS-(±)-Nadifloxacin derives its biological activity primarily from the S-(−)-enantiomer. The optically active S-(−)-Nadifloxacin[α]20D=−312.0 is obtained as disclosed in Chem. Pharm. Bull 44 (1996), page nos. 642-5 and Jpn. Kokai Tokyo Koho JP 63,192,753. The optically active R-(+)-Nadifloxacin, [α]20D=+312.0, is obtained as disclosed in Jpn. Kokai Tokyo Koho JP 63,192,753. Pharmaceutical compositions of RS-(±)-Nadifloxacin are disclosed in U.S. Pat. No. 4,399,134 and U.S. Pat. No. 4,552,879. Although these cited patents disclose compositions of RS-(±)-Nadifloxacin for oral, parenteral and topical use, the only commercial product containing RS-(±)-Nadifloxacin as an active antibacterial compound is the commercial product named Acuatim®. Acuatim® is available as a cream and a lotion and incorporates racemic RS-(±)-Nadifloxacin as 1% of its composition for the topical treatment of acne. Acuatim® has several drawbacks. It is intended only for topical use and is registered only for the treatment of acne caused by Propionibacterium species. One report has appeared on the in-vitro activity of the fluoroquinolone, Nadifloxacin, against methicillin resistant isolates of Staphylococcus aureus from patients with skin infections (see Nishijima et al., Drugs 49 (Suppl.) 230-232, 1995). There is no report of RS-(±)-Nadifloxacin being approved for systemic use against any microbial infections, whether for sensitive or resistant microbial strains.
S-(−)-Nadifloxacin is reported in Chem. Pharm, Bull 44 (1996) pages Nos. 421-423 to be approximately twice as active in-vitro as racemic Nadifloxacin against Gram-positive and Gram-negative bacteria. There is no previous report, however, of the activity of S-(−)-Nadifloxacin in in-vivo systems against Gram-positive bacteria, Gram-negative bacteria, anaerobes, mycobacteria and emerging nosocomial pathogens.
RS-(±)-Nadifloxacin is reported to exist in two crystalline forms, one as an anhydrate and the other as a hemihydrate (M. Kido and K. Hashimoto, Chem. Pharm. Bull, 42, 872 (1994)). There is no previous report, however, of any hydrate forms of S-(−)-Nadifloxacin, although a non-hydrate form is reported (K. Hashimoto et al., Chem. Pharm. Bull., 44,642 (1996)).
There is no previous report of the utility of optically pure benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof of the invention in pharmaceutical compositions. There is also no previous report of the systemic or topical use of optically pure benzoquinolizine carboxylic acids, their derivatives, salts and hydrates thereof of the invention, either alone or in compositions for treatment of microbial infections diseases or disorders.
Our pending PCT patent application No. PCT/IN99/00016 filed on May 7, 1999 describes optically pure and racemic benzoquinolizine carboxylic acids, derivatives and salts thereof for treatment of infections caused by Mupirocin-resistant bacterial strains such as Mupirocin-resistant staphylococci, Mupirocin-resistant streptococci and other Mupirocin-resistant Gram-positive and Mupirocin-resistant Gram-negative bacteria, and for treatment of dermal diseases such as impetigo, folliculitis, infected dermatitis, wounds and burns. The subject matter of PCT application PCT/IN99/00016 is incorporated herein by reference.